Macrophage-dependent cleavage of the laminin receptor ?6?1 in prostate cancer.

ABSTRACT: The laminin-binding integrin ?6?1 plays a major role in determining the aggressive phenotype of tumor cells during metastasis. Our previous work has shown that cleavage of the ?6?1 integrin to produce the structural variant ?6p?1 on tumor cell surfaces is mediated by the serine protease urokinase plasminogen activator (uPA). Cleavage of ?6?1 increases tumor cell motility, invasion, and prostate cancer metastasis, and blockage of uPA inhibits ?6p?1 production. In human tumors, uPA and uPAR are expressed in tumor cells and tumor-associated macrophages (TAM). TAMs localize to solid tumors and contribute to increased tumor growth and the metastatic phenotype. In this study, we utilized a coculture system of PC-3 prostate tumor cells and macrophages [12-O-tetradecanoylphorbol-13-acetate (TPA)-differentiated human leukemia HL-60 cells] to investigate the hypothesis that macrophages stimulate the production of the prometastatic variant ?6p?1 on human prostate cancer cells via the uPA/uPAR axis. Our results indicate that adherent macrophages cocultured with PC-3 cells increased PC-3 uPAR mRNA, uPAR cell surface protein expression and ?6 integrin cleavage. The stimulation does not require macrophage/tumor cell contact because macrophage conditioned medium is sufficient for increased uPAR transcription and ?6 cleavage-dependent PC-3 cell invasion. The increased cleavage was dependent on uPAR because production was blocked by silencing RNA-targeting uPAR. These results indicate that macrophages can stimulate uPA/uPAR production in tumor cells which results in ?6 integrin cleavage. These data suggest that TAMs promote prometastatic integrin-dependent pericellular proteolysis.

SUBMITTER: Sroka IC 

PROVIDER: S-EPMC3196809 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature